Cocaine dependence is an important public health problem with over 1.7 million users in the US alone. In spite of ongoing efforts, no medications have been approved for the treatment of cocaine dependence yet. Thus, development of effective pharmacotherapies for cocaine dependence remains an important goal. Among potentialtargets for cocainepharmacotherapy, the gamma-aminobutyric acid (GABA) system has received increasing attention in both preclinical and clinical studies. In preclinical studies, medications which increased GABA effects attenuated cocaine self-administration. Similarly, a number of clinical trials testing the efficacy of GABA medications for cocaine dependence showed promising findings. These preclinical and clinical studies suggest that medications act on the brain GABA system may have utility for cocaine pharmacotherapy. The goal of this proposal is to determine the potential utility of selected GABA medications for cocaine pharmacotherapy by examining their interactions with cocaine in human laboratory settings. The GABA medications included in this proposal are tiagabine, topiramate, valproic acid, baclofen and progesterone. In each study, 12 cocaine users will have experimental sessions following placebo and active medication treatment. The medications will be given in escalating doses over 3 days to attain therapeutic levels while maintainingmedical safety and minimizing side effects. During the sessions, subjects will receive escalating doses of cocaine to examine the effects of GABA medications on the cardiovascular and subjective-rewarding responses to cocaine. The medications selected have diverse effects on the GABA system and are potential medications for future cocaine pharmacotherapy trials. Theproposed studies will provide essential safety information for selected GABA medications by systematically examining their interactions with dose-dependent cardiovascular and subjective-rewarding effects of cocaine. The results of this study willprovide new insight on the interaction between the GABA system and cocaine effects and will guide future pharmacotherapy trials using GABA medications.